DRUG DELIVERY SYSTEMS COMPRISING WEAKLY BASIC DRUGS AND ORGANIC ACIDS

Abstract

A pharmaceutical dosage form such as a capsule, a conventional or orally disintegrating tablet capable of delivering a nitrogen (N)-containing therapeutic agent having a pKa in the range of from about 5 to 14 into the body in a sustained-released fashion, in order to be suitable for a twice- or once-daily dosing regimen, comprises at least one organic acid, which solubilizes the therapeutic agent the drug prior to releasing it into the hostile intestinal environment wherein said weakly basic drug is practically insoluble. The unit dosage form is composed of a multitude of multicoated particulates (i.e., immediate-release beads, sustained-release beads and/or one or more timed, pulsatile-release bead populations) is designed in such a way that said weakly basic drug and said organic acid do not come into close contact during processing and/or storage for in-situ formation of acid addition compounds while ensuring that the acid is not depleted prior to completion of the drug release.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates pH-solubility profiles for (a) Ondansetron hydrochloride, (b) Carvedilol, (c) Dipyridamole, and (d) Clonazepam;

FIG. 2 illustrates a cross-section of an SR coated organic acid-containing core in accordance with one aspect of the invention;

FIG. 3 illustrates a cross-section of a TPR bead comprising an SR coated organic acid-containing core in accordance with a particular aspect of the invention;

FIG. 4 illustrates the release of fumaric acid from SR-coated acid crystals coated at different ratios of EC-10/PEG of Example 1;

FIG. 5 illustrates the release profiles of dipyridamole from TPR beads of Example 2E;

FIG. 6 illustrates the release profiles of carvedilol TPR beads of Example 5 versus Comparative Example 4B;

FIG. 7 illustrates the release profiles of ondansetron hydrochloride from TPR beads on stability (Example 5);

FIG. 8 illustrates the release profiles of ondansetron hydrochloride from TPR beads coated at different ratios of EC-10/HP-55/TEC at 50% by weight of Example 5; and

FIG. 9 illustrates the plasma concentration—time profiles of ondansetron HCl Test Formulations (QD) and Zofran 8 mg (BID) of Example 7.

Claims

1. A pharmaceutical multiparticulate dosage form comprising immediate release (IR) beads, one or more populations of sustained-release (SR) beads and/or one or more populations of timed, pulsatile release (TPR) beads of at least one weakly basic drug, wherein the weakly basic drug comprises a pharmaceutically acceptable nitrogen (N)-containing therapeutic agent having a pKa in the range of from about 5 to 14, and a solubility of not more than about 200 μg/mL at pH 6.8 and at least one pharmaceutically acceptable organic acid as a solubilizer wherein the weakly basic therapeutic agent and the organic acid do not come into contact with each other during manufacturing or in storage in the solid state thereby avoiding in-situ formation of an acid addition compound and the organic acid is not depleted until completion of the drug release from the dosage form when dissolution tested by United States Pharmacopoeia (USP) dissolution methodology using a two-stage dissolution medium (first 2 hours in 0.1N HCl followed by testing in a buffer at pH 6.8).

2. A pharmaceutical multiparticulate dosage form in accordance with claim 1 wherein the ratio of optimal highest dose for the weakly basic drug to solubility at pH 6.8 is not less than about 100, and at least one pharmaceutically acceptable organic acid solubilizes said weakly basic drug prior to releasing it into a hostile intestinal environment wherein said weakly basic drug is practically insoluble, and said dosage form exhibits target pharmacokinetics profiles at 12-24 hour post-dosing suitable for a twice- or once-daily dosing regimen in patients in need of such a medication.

3. A pharmaceutical multiparticulate dosage form in accordance with claim 1 wherein: a) said TPR bead comprises an outer lag-time coating comprising a water-insoluble polymer in combination with an enteric polymer applied over said SR bead, said outer coating providing a lag time of from about 2 to about 7 hours before onset of drug release;b) said SR bead comprises an SR (barrier) coating surrounding an IR bead, said barrier coating comprising a water-insoluble polymer alone or in combination with a water-soluble pore-forming polymer, said SR membrane providing a sustained-release profile;c) said IR bead comprises at least one weakly basic drug applied on a barrier (SR)-coated organic acid core particle;d) said barrier-coated organic acid core comprises an inner barrier coating surrounding an organic acid core particle, said inner barrier coating comprises a water-insoluble polymer alone or in combination with a water-soluble polymer or an enteric polymer wherein said inner barrier coating provides a sustained-release profile; ande) said organic acid core particle comprises at least one pharmaceutically acceptable organic acid functioning as a solubilizer of said weakly basic drug;

4. A pharmaceutical multiparticulate dosage form in accordance with claim 1 in the form of an orally disintegrating tablet (ODT) further comprising rapidly-dissolving microgranules with an average particle size of not more than 400 μm comprising a disintegrant and a sugar alcohol or a saccharide or a combination thereof, each having an average particle size of not more than about 30 μm wherein said orally disintegrating tablet exhibiting the following properties: i. a friability of less than 1% by weight; andii. a disintegration time of about 60 seconds or less on contact with the saliva in the oral cavity forming a smooth suspension comprising multicoated beads.

5. A pharmaceutical multiparticulate dosage form in accordance with claim 3 wherein said TPR beads do not include a barrier (SR) coating on said IR beads thereby enabling the release of solubilized drug into a hostile intestinal environment wherein the drug is practically insoluble following oral administration in order to be suitable for a once-daily dosing regimen in patients in need of such a medication.

6. A pharmaceutical multiparticulate dosage form in accordance with claim 1 comprising at least an IR bead population, a first TPR bead population and an SR bead population or a second TPR bead population wherein the ratio of IR bead to the first TPR bead to the SR bead or to the second TPR bead populations varies from about 10:90:0 to about 40:10:50.

7. A pharmaceutical multiparticulate dosage form in accordance with claim 1 wherein said weakly basic, nitrogen (N)-containing therapeutic agent having a pKa in the range of from about 5 to 14 and a solubility of not more than about 200 μg/mL at pH 6.8, is selected from the group consisting of analgesics, anticonvulsants, antidiabetic agents, anti-infective agents, antineoplastics, antiParkinsonian agents, antirheumatic agents, cardiovascular agents, CNS (central nervous system) stimulants, dopamine receptor agonists, anti-emetics, gastrointestinal agents, psychotherapeutic agents, opioid agonists, opioid antagonists, anti-epileptic drugs, histamine H2 antagonists, anti-asthmatic agents, and skeletal muscle relaxants.

8. A pharmaceutical multiparticulate dosage form of claim 7 wherein said weakly basic, nitrogen (N)-containing therapeutic agent is selected from the group consisting of olanzapine, ondansetron, ondansetron hydrochloride, dipyridamole, carvedilol, lamotrigine, olanzapine, quetiapine, pharmaceutically acceptable salts thereof and combinations thereof.

9. A pharmaceutical multiparticulate dosage form in accordance with claim 1 wherein the organic acid is selected from the group consisting of citric acid, fumaric acid, malic acid, maleic acid, tartaric acid, succinic acid, oxalic acid, aspartic acid, glutamic acid and mixtures thereof.

10. A pharmaceutical multiparticulate dosage form in accordance with claim 1 wherein the ratio of weakly basic drug to organic acid varies from about 5:1 to 1:10 by weight to provide target pharmacokinetic profiles suitable for a once-daily dosing regimen.

11. A pharmaceutical multiparticulate dosage form in accordance with claim 3, wherein said organic acid core particle comprises: i. an organic acid crystal;ii. inert particle coated with an organic acid and a polymer binder; oriii. a pellet or a micro-tablet containing the organic acid, a polymer binder and a diluent/filler, prepared by rotogranulation, granulation-extrusion-spheronization or granulation-compression.

12. A pharmaceutical multiparticulate dosage form in accordance with claim 11 wherein said IR bead comprises a drug layer comprising a polymeric binder at a drug to binder ratio of from about 85:15 to about 99:1 and said polymeric binder is selected from the group consisting of polyvinylpyrrolidone, methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, corn starch, pre-gelatinized starch and mixtures thereof.

13. A pharmaceutical multiparticulate dosage form in accordance with claim 3 wherein said particle core is provided with a barrier (SR) coating comprising a water-insoluble polymer alone or in combination with a water soluble polymer at a ratio of from about 9:1 to 5:5 wherein said barrier coating is applied for a weight gain of from about 1.5% to 20% by weight based on the weight of the coated bead.

14. A pharmaceutical multiparticulate dosage form in accordance with claim 11 wherein said particle barrier coating comprises a water-insoluble polymer selected from the group consisting of ethylcellulose, cellulose acetate, cellulose acetate butyrate, polyvinyl acetate, neutral methacrylic acid-methylmethacrylate copolymers, and mixtures thereof.

15. A pharmaceutical multiparticulate dosage form in accordance with claim 11 wherein said particle core is provided with a barrier coating comprising a water-insoluble polymer alone or in combination with a water soluble polymer selected from the group consisting of methylcellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinyl pyrrolidone and polyethylene glycol and mixtures thereof.

16. A pharmaceutical multiparticulate dosage form in accordance with claim 3 wherein said lag-time coating comprises a water-insoluble polymer in combination with an enteric polymer at a ratio of from about 9:1 to 1:3, respectively, for a weight gain of from about 10% to 60% by weight based on the weight of the TPR bead.

17. A pharmaceutical multiparticulate dosage form in accordance with claim 14 wherein said lag-time coating comprises a water-insoluble polymer in combination with an enteric polymer selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose succinate, polyvinyl acetate phthalate, pH-sensitive methacrylic acid-methylmethacrylate copolymers, shellac, derivatives thereof, and mixtures thereof.

18. A pharmaceutical multiparticulate dosage form in accordance with claim 3 wherein at least one of the inner barrier coatings and the outer lag-time coating comprises a plasticizer selected from the group consisting of triacetin, tributyl citrate, tri-ethyl citrate, acetyl tri-n-butyl citrate, diethyl phthalate, dibutyl sebacate, polyethylene glycol, polypropylene glycol, castor oil, acetylated mono- and di-glycerides and mixtures thereof.

19. A pharmaceutical multiparticulate dosage form of claim 3 wherein said IR beads provide a loading dose by releasing not less than about 50% of the active contained in said IR beads within the first hour after oral administration of the dosage form.

20. A pharmaceutical multiparticulate dosage form of claim 3 wherein said IR bead, if incorporated as an IR portion of the dosage form, comprises said weakly basic drug and a polymer binder layered on an inert core.

21. A pharmaceutical multiparticulate dosage form in accordance with claim 1 wherein said weakly basic drug comprises carvedilol or pharmaceutically acceptable salt thereof, and each TPR bead population comprises sustained-release coated tartaric acid cores coated with a lag-time coating of water-insoluble ethylcellulose and enteric hydroxypropyl methylcellulose phthalate at a ratio of from about 9:1 to about 1:3 for a weight gain of up to 50%, exhibiting upon oral administration of the dosage form a pre-determined lag-time followed by differing release characteristics.

22. A pharmaceutical multiparticulate dosage form in accordance with claim 1 wherein said weakly basic drug comprises ondansetron or pharmaceutically acceptable salt thereof, and each TPR bead population comprises sustained-release coated fumaric acid cores coated with a lag-time coating of water-insoluble ethylcellulose and enteric hydroxypropyl methylcellulose phthalate at a ratio of from about 9:1 to about 1:3 for a weight gain of up to 50%, exhibiting upon oral administration of the dosage form a pre-determined lag-time followed by differing release characteristics.

23. A pharmaceutical multiparticulate dosage form in accordance with claim 1 wherein said orally disintegrating tablet comprises a taste-masked IR bead population, an SR bead population, and/or one or two TPR bead populations of a weakly basic, nitrogen (N)-containing therapeutic agent having a pKa in the range of from about 5 to 14 or pharmaceutically acceptable salt thereof, wherein each SR or TPR bead population comprising sustained-release coated fumaric acid cores, rapidly disintegrates in the oral cavity creating a smooth, easy-to-swallow suspension of multi-coated beads to provide target pharmacokinetics profiles suitable for a once- or twice-daily dosing regimen in patients in need of such a medication.

24. A method for the preparation of a multiparticulate dosage form comprising a weakly basic, nitrogen (N)-containing therapeutic agent having a pKa in the range of from about 5 to 14 and a solubility of not more than about 200 μg/mL at pH 6.8, and at least one pharmaceutically acceptable organic acid as a solubilizer comprising: a. preparing organic acid cores;b. preparing barrier-coated organic acid cores by coating the organic acid cores with a barrier-coating comprising a polymer, more particularly comprising a water-insoluble polymer alone or in combination with a water-soluble polymer or an enteric polymer at a ratio of from about 95/5 to about 50/50 for a weight gain of up to about 20%, to provide a sustained-release profile;c. preparing IR (immediate-release) beads by layering the one or more weakly basic or pharmaceutically acceptable salts thereof from a polymer binder solution onto the barrier-coated organic acid cores and optionally applying a protective seal-coat with a water-soluble polymer;d. preparing SR beads by applying a barrier (SR) coating of a water-insoluble polymer alone or in combination with a water-soluble polymer at a ratio of from about 95:5 to about 50:50 for a weight gain of from about 1.5% to 20% by dry weight of the coated bead;e. preparing TPR beads by applying an outer lag-time coating comprising a water-insoluble polymer in combination with an enteric polymer at a ratio of from about 9:1 to 1:3 for a weight gain of from about 10% to 60% by weight of the coated bead; andf. filling into a gelatin capsule or compressing into a conventional tablet or an orally disintegrating tablet a mixture of IR beads, SR beads and/or one or more TPR bead populations at appropriate amounts to achieve target pharmacokinetics profiles in order to be suitable for a once-daily dosing regimen in patients in need of such a medication. pharmacokinetics profiles in order to be suitable for a twice- or once-daily dosing regimen in patients in need of such a medication.

25. A method in accordance with claim 22, wherein each of said organic acid-layering, SR-coating, drug-layering and outer lag-time coating is applied from a solution in a pharmaceutically acceptable solvent system or from an aqueous dispersion.

26. A method in accordance with claim 22 further comprising the following steps: i. optionally taste-masking drug-containing beads either by solvent coacervation or by fluid-bed coating;ii. optionally providing a compressible coating on IR beads, SR beads and/or TPR beads with a plasticized polymer to eliminate/minimize membrane fracture during compression;iii. granulating a sugar alcohol or a saccharide, or a combination thereof, and a disintegrant, each having an average particle size of not more than about 30 μm to produce rapidly dispersing microgranules with an average particle size of not more than about 400 μm;iv. blending the multi-coated beads with the rapidly dispersing microgranules at a ratio of multi-coated beads to microgranules from about 1:6 to about 1:2; andv. compressing the blend into orally disintegrating tablets on a conventional rotary tablet press.

27. A method in accordance with claim 24, wherein said step of compressing may comprise utilizing a conventional rotary tablet press equipped with an external lubrication system to lubricate the dies and punches prior to compression.

28. method of claim 22 wherein the dosage form comprises therapeutically effective amounts of IR bead population, SR bead population and/or one or more TPR bead populations of a weakly basic, nitrogen (N)-containing therapeutic agent, each multicoated bead population exhibiting differing release characteristics following a pre-determined lag-time.